The present invention relates to novel solid compositions, notably pharmaceutical compositions, containing polyethylene oxide and an active ingredient, and to methods for their preparation.
Certain medicaments need to be formulated in so-called delayed-release or sustained release form.
Polyethylene oxide referred to as PEO below is moreover known as a component of medicaments in tablet form designed to be administered by oral route. This compound is marketed by the Union Carbide Corporation under the commercial name Polyox(copyright) . The use of PEO for formulating medicaments has furthermore been the subject matter of many earlier patents.
EP-A-0 277 092, in the name of Ciba-Geigy relates to a composition comprising a casing in a material that is porous to water but not to the active ingredient, surrounding a central core consisting of a mixture of a substance that is weakly soluble in water, and a hydrophilic swelling material, said material consisting of a mixture of PEO and a vinyl pyrrolidone/vinyl acetate polymer. The composition in that patent is an example of current compositions in which a core which swells when exposed to water is surrounded by a water-porous material, release of the active ingredient being delayed or sustained as a result of the time necessary to expand the core, and for diffusion to take place through the casing following the penetration of water.
The abstract of the U.S. Pat No. 4,404,183 and U.S. Pat. No. 4,343,789 discloses two embodiments of a sustained release composition. In the first embodiment, the composition contains PEO, the active ingredient in an amorphous form, and a basic component. In the second embodiment, the active ingredient is nicardipine in an amorphous state, it being possible to omit the basic component.
Actually, the compositions according to the prior art are complex, require specific active ingredients or are provided in a specific form. Moreover, the results achieved are not always very good.
The present invention provides a simple composition which is suitable for use with a multiplicity of active ingredients, and has a remarkable delaying or sustaining effect.
Thus, the present invention provides a solid composition comprising, by weight based on the total weight of the composition:
(a) from 1 to 70% of an active ingredient which is not in an amorphous form;
(b) from 10 to 95% of polyethylene oxide;
(c) the balance consisting of conventional additives, excluding basic components.
The expression xe2x80x9csolid compositionxe2x80x9d means that the composition is in a tablet or mini-tablet form, these in their turn being able to be encapsulated using for example the conventional hard gelatin.
The expression xe2x80x9cactive ingredientxe2x80x9d should be understood in its normal sense and, generally speaking, covers medicaments for treatment of the human or animal body as well as an association of one or several such medicaments. Active ingredients that are either hydrophilic or lipophilic are envisaged.
The expression xe2x80x9cnot in amorphous formxe2x80x9d should be understood in its conventional meaning. Various sources give a definition of this term xe2x80x9camorphousxe2x80x9d as meaning non-crystalline, lacking the lattice structure characterizing the crystalline state. The following references, which provide a definition of the term amorphous (or the opposite thereof) are, in a on-limiting manner : Hawley""s, Condensed Chemical Dictionary, 12th Edition, p. 71; Handbook of Chemistry and Physics, 65th Edition, F-67; The Theory and Practice of Industrial Pharmacy, 1970, pp. 253-255; Remington""s Pharmaceutical Sciences, 14th Edition, p. 182; General Chemistry 1992, pp.314-315; Encyclopedia of Pharmaceutical Technology, vol I, pp. 12-13.
The expression xe2x80x9cexcluding basic compoundsxe2x80x9d should be understood as excluding the presence of a compound or a group of compounds that confer a basic nature on the composition, in other words a pH greater than 7, when the composition is diluted in water at a rate of 10 g per liter of water. In particular, this term should be taken as excluding the presence of one or several basic component(s) such as described in column 1, lines 38 to 62 of U.S. Pat. No. 4,404,183 if no acid compound is counteracting the effect of said basic compound, or if the basic compound is present in a relatively large amount.
According to one preferred embodiment, the composition according to the invention, comprises:
(a) from 5 to 45% of an active ingredient;
(b) from 25 to 70% polyethylene oxide
(c) the balance consisting of conventional additives, excluding basic components.
According to one preferred embodiment of the composition according to the invention, the active ingredient is a hydrophilic or lipophilic active ingredient, advantageously a hydrophilic ingredient.
According to another preferred embodiment of the composition according to the invention, the active ingredient is selected from the group comprising acyclovir, nifedipine, nicardipine, captopril, verapamil, diltiazem, oxybutynine, valacyclovir, glipizide, felodipine, isosorbide, carbidopa, levodopa, pentoxiphylline, and their pharmaceutically acceptable salts.
According to one alternative embodiment, in the composition according to the invention, the polyethylene oxide has a molecular weight which varies from 50,000 to 8,000,000, and preferably from 100,000 to 3,000,000. The required molecular weight for the PEO can be obtained by mixing PEO of differing molecular weights, that are available commercially.
According to a further embodiment, in the composition according to the invention, the balance consisting of conventional additives comprises microcrystalline cellulose, lactose, ascorbic acid, pigments, plastifying agents, lubricants and so on. Obviously, other conventional additives known to those skilled in the art can be employed.
According to one embodiment of the invention, in a composition, the balance consisting of conventional additives comprises magnesium stearate and/or glycerol behenate and/or sodium stearyl fumarate, which is employed as a lubricant ensuring better compression of the composition when provided in tablet form, for example.
According to one or alternative embodiment, the composition is additionally coated. Surface coating is employed for the purposes of improving appearance making the drug more readily acceptable to the patient, or for dimensionally stabilising the compressed tablet. The coating can be a conventional coating suitable for enteral use. It is obtained using any conventional technique employing conventional ingredients. A surface coating can for example be obtained using a quick-dissolving film. It should be noted that the coating according to this invention is fundamentally different from the coating used in EP-A-0,277,092 as one does not encounter, in the invention, the dichotomy (water-swellable core)/(water-porous coating), and moreover, the coating in the invention dissolves and/or disintegrates whereas the coating in EP-A-0,277,092 does not dissolve.
According to another embodiment, the coating is functional. This functional coating comprises a functional coating which comprises, based on the weight of the coating, from 30 to 80% of a gastroresistant polymer and from 10 to 40% of a hydrophilic silicon dioxide.
The gastroresistant polymer withstands the acidic medium of the stomach and the duodenum, but will dissolve in the intestines, as soon as the pH reaches a predetermined level (e.g. above 5.5 or above 7). This gastroresistant polymer can be selected from the group consisting in (uncured) poly(meth)acrylic acid, cellulose and alkylcellulose-phtalates. Molecular weight can vary within broad limits as will recognize the skilled man. The term xe2x80x9cuncuredxe2x80x9d is used to differentiate over U.S. Pat. No. 5,580,578.
Preferably, it is of the type of Eudragit L30D55. One preferred polymer is an anionic copolymer on the basis of methacrylic acid and acrylic acid ethyl ester. The formula is as follows: 
The ratio free carboxyl group to ester group is preferably about 1:1. The mean molecular weight is e.g. about 250,000.
Such a copolymer will easily dissolve at pH values above 5.5 with the forming of salts.
Hydrophilic silicon dioxide is a known hydrophilic anti-tacking agent, the definition of which is known to the skilled man and can be found in the literature.
The functional coating may further comprise polyethyleneglycol, present in an amount from 5 to 30% by weight, based on the total weight of the functional coating. Stearic acid, dibutyl sebacate, propylene glycol and/or triethyl citrate can used in lieu of or in addition to polyethyleneglycol.
The functional coating usually represents from 0.5 to 6% by weight of the core weight.
The present solid compositions are suitable for the administration of medicaments. Thus, the invention also relates to pharmaceutical compositions deriving therefrom as well as to compositions thereof for use as medicaments.
The present composition can be obtained by any conventional method known to those skilled in the art such as, for example direct compression after simply mixing the dry ingredients, moist or wet granulation involving the use of a granulation liquid, and dry granulation involving a densification phase for the dry mixture.
However, use is preferably made of a process comprising the steps of:
(i) mixing in the dry state and for a sufficient time, the active ingredient, polyethylene oxide and optionally, one or several additives;
(ii) optionally adding solvent when this is used, followed by mixing for a sufficient period of time;
(iii) granulation by passage through a suitable sieve;
(iv) drying the granules thus formed for a sufficient period of time;
(v) optionally adding one of more additives, with mixing in the dry state for a sufficient time and passage through a suitable sieve;
(vi) optionally adding one or several additives and mixing in the dry state for a sufficient period of time;
(vii) compressing the mixture obtained from the preceding steps to obtain the desired compressed tablet; and
(viii) optionally coating said compressed tablet.
The solvent employed, when use is made of a solvent, is preferably an alcohol. The solvent is eliminated by drying at one point or another in the process, and is substantially not encountered in the final composition.
The choice of mixing times, apparatus used, sieve mesh, and other operating conditions are within the province of the normal knowledge of those skilled in the art.
The invention will now be described in more detail, with reference to FIG. 1 which shows percentage in-vitro release of an active ingredient as a function of time for the solid compositions of examples 1 and 2.
Without wishing to be bound by any theory, the applicant believes that the PEO, in the formulation, forms a hydrogel from contact with water. This hydrogel dissolves more or less rapidly as a function of the molecular weight of the PEO employed. Choosing the molecular weight of the PEO, in combination with a suitable choice of the weight concentrations of the active ingredient, of PEO, and of additives enables release of the active ingredient to be controlled.
Moreover, the present composition exhibits particularly surprising results. In a hydrophilic matrix, when the concentration of the hydrophilic active ingredient increases, one would expect that the rate of release of the active ingredient would increase. The present composition exhibits the opposite effect, in the case, for example, of acyclovir as active ingredient. This is clearly shown in FIG. 1, which gives in-vitro dissolution of the compositions of examples 1 and 2. The composition of example 1 has a lower concentration of the active ingredient (200 mg medicament in a 905 mg tablet) and shows a faster in-vitro release of the drug as compared to the formulation of example 2 which has a higher concentration of the active ingredient (400 mg of medicament in a 905 mg tablet). This result is particularly surprising.
The examples below are provided as examples illustrating the invention and should not be considered as limiting its scope. In the examples, the amount of solvent employed is given in brackets, it being understood that the solvent is substantially absent in the final composition.